Chronic bronchopulmonary infections are the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Pseudomonas aeruginosa is the predominant respiratory tract pathogen in patients with cystic fibrosis leading to progressive pulmonary deterioration. Treatments utilizing polysaccharides for the treatment of P. aeruginosa infection in CF patients have been suggested but are not yet in general use. In vitro experiments have shown that dextran can inhibit the adherence of P. aeruginosa to epithelial cells (Barghouthi et al, Am. J. Respir. Crit. Care Med. 1996, 154:1788-1793) and that xylitol has antimicrobial effects on coagulase negative staphyloccus (Zabner et al., PNAS, 2000, 97:11614-11619). U.S. Pat. No. 5,441,938 is directed to the use of D-glucose or D-mannose in the treatment or prevention by P. aeruginosa in cystic fibrosis patients. U.S. Pat. No. 5,514,665 is directed to methods and compositions using the polysaccharides dextran sulfate or dextran for the treatment of P. aeruginosa infection in vivo in compromised hosts such as cystic fibrosis patients. Polyols such as xylitol have also been used in methods of treating S. pneumoniae respiratory infections as is disclosed in U.S. Pat. Nos. 5,719,196, 6,066,677 and 6,143,330.
Although Pseudomonas aeruginosa is the major opportunistic respiratory pathogen isolated from CF patients, a subgroup of these patients (3-5% globally) also becomes infected with Burkholderia cepacia which is a particularly infectious bacterial species that is resistant to killing by standard antimicrobial preparations. In North America, the prevalence is about 8-10% and is much higher in the certain clinics such as the Toronto adult CF clinic (46%). The clinical outcome of B. cepacia-infected patients is unpredictable and varies widely, from no adverse effects to fatal necrotizing pneumonia within a few months of infection (cepacia syndrome) or after being colonized for several years.
B. cepacia is a common soil- and water-borne Gram negative bacterium known to infect not only patients with CF, but also patients with chronic granulomatous disease (CGD) (Govan J. R., Deretic V. Microbiol. Rev. September 1996;60(3):539-74). B. cepacia is highly resistant to killing by cationic antimicrobials such as aminoglycosides, polymyxin B, and defensins due to the low levels of negatively-charged phosphate residues in the core region of its outer membrane. This property allows it to readily infect CGD patients, whose neutrophils lack the capacity to generate bacteriocidal oxygen radicals and rely only on non-oxidative cationic-peptide-based bacteriocidal mechanisms (Speert D. P., Bond M, Woodnian R. C., Curnutte T. J. Infectious Diseases. December 1994; 170(6):1524-31). In addition in its resistance to cationic antibiotics, B. cepacia is also highly resistant to most other antibiotics (Govan J. R., Hughes J. E., Vandamme P. J Med. Microbiol. December 1996.;45(6):395-407), necessitating the use of near-toxic antibiotic doses for therapy.
B. cepacia is a complex organism and has been classified into more than 8 genomovars based on phenotypic and genotypic characteristics. The strains most commonly isolated from CF patients belong to genomovars II, III and IV. B. cepacia-colonized patients in eastern Canada and the U.K. carry a highly transmissible strain of genomovar III commonly known as ET12, and this strain has been linked to the fatal cepacia syndrome in CF centers. This strain expresses giant surface pili designated cable pili, and a 22 kDa adhesin protein associated with these pili mediates the adherence of bacteria to airway epithelia and luminal mucus.
Lung transplantation is accepted as a treatment for CF patients with end stage lung disease. Each year, a major proportion of lung transplants performed in large centres such as Toronto are in CF patients. Many transplant centers refuse to perform this procedure on B. cepacia infected patients, since the 5-year survival rates of such patients is low compared with survival rates for patients previously colonized by P. aeruginosa. Prognosis following transplantation is poor in patients colonized with B. cepacia prior to lung transplantation and the one year survival rate is only 61%, which is lower than patients not colonized with this organism (88%). This problem is made worse by the facts that lung transplant recipients are immunosuppressed and B. cepacia is intrinsically resistant to multiple antibiotics.
In addition to the problem of B. cepacia resistance to antibiotics, it is well recognized that damaged airway epithelium has increased susceptibility to invasive bacterial infection. Thus, after transplantation in CF patients, one is faced with an injured airway epithelium, a pan-resistant, aggressively invasive organism and an immunosuppressed host—all of which translate into significantly increased infectious morbidity and mortality in this group. Although post-transplantation antibiotic strategies have improved the survival rate for B. cepacia-infected patients, other strategies are clearly needed to further improve the prognosis and prevent the infection and reinfection of lung allografts by B. cepacia and other organisms in transplant patients, including cystic fibrosis patients.